Treatments for depression and other diseases with a low dose agent

ABSTRACT

The present invention relates to improved compositions and methods for the treatment or prevention of various diseases, including forms of depression, including, for example, breakthrough depression and treatment-refractory depression, and other mood disorders, as well as Parkinson&#39;s disease, bipolar disorder, bipolar disorder, attention deficit disorder (ADHD), Restless Leg Syndrome (RLS), and obesity. In some embodiments, the compositions and methods comprise low dose naltrexone or related opioid antagonists.

PRIORITY

The present application is a continuation-in-part of U.S. patentapplication Ser. No. 14/410,551, which, on Dec. 22, 2014, entered theU.S. National Stage of International Patent Application No.PCT/US2014/013874, filed Jan. 30, 2014, which claims priority to U.S.Provisional Application No. 61/758,551, filed on Jan. 30, 2013 and U.S.Provisional Application No. 61/814,476, filed on Apr. 22, 2013, thecontents of which are herein incorporated by reference in theirentireties. The present application is related to U.S. patentapplication Ser. No. 12/603,235, filed Oct. 21, 2009 and U.S. patentapplication Ser. No. 13/758,569, filed Feb. 4, 2013, the contents ofwhich are incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to compositions and methods that areuseful in treating various forms of depression and other disorders.

BACKGROUND

Mental illnesses and obesity are increasing prevalent disorders in themodern world and require improved treatments to maximize patient qualityof life and reduce health care costs.

For instance, depression refers to a serious medical illness thataffects one's thoughts, feelings, behavior, mood and physical health.Major depression, also referred to as clinical depression, majordepressive illness, major affective disorder and unipolar mood disorder,may involve some combination of the following symptoms: depressed mood(sadness), poor concentration, insomnia, fatigue, appetite disturbances,excessive guilt and thoughts of suicide. Left untreated, depression canlead to serious impairment in daily functioning and even suicide.Suicide is the tenth leading cause of death in the U.S. Researchersbelieve that more than one-half of people who die by suicide areexperiencing depression. Each year depression affects 5-8 percent ofadults in the United States. Therefore, about 25 million Americans willhave an episode of major depression this year alone. Without treatment,the frequency and severity of depression symptoms tend to increase overtime.

Furthermore, attention deficit hyperactivity disorder (ADHD) is one ofthe most common childhood disorders and can continue through adolescenceand adulthood. Symptoms include difficulty staying focused and payingattention, difficulty controlling behavior, and hyperactivity(over-activity). Parkinson's disease is a degenerative disorder of thecentral nervous system with marked motor symptoms linked, in part, tothe death of dopamine-generating cells. Common symptoms of this disorderare movement-related, including shaking, rigidity, slowness of movementand difficulty with walking and gait. Behavioral problems and dementiaare also common, particularly in late stage disease. Bipolar disorderdescribes a brain disorder that causes unusual shifts in mood, energy,activity levels, and the ability to carry out day-to-day tasks.

Obesity is a disorder marked by excessive body fat that negativelyaffects a patient's health. If a person's bodyweight is at least 20%higher than it should be, he or she is considered obese. Obesity islinked to a panoply of diseases, including coronary heart disease, type2 diabetes, cancers (e.g., endometrial, breast, and colon),hypertension, dyslipidemia, stroke, liver and gallbladder disease, sleepapnea and respiratory problems, osteoarthritis, and gynecologicalproblems, among others.

Unfortunately, sufficient treatment for these disorders has provenelusive. For instance, in the context of depression, while certainpharmaceuticals have proven somewhat successful, medical practitionersface the challenge of unpredictable responses and eventual loss ofeffect, necessitating constant evaluation of treatments and, often,changes in treatment regimens. Further, anti-depression pharmaceuticalsare often characterized by unpleasant side effects.

Therefore, there remains a need for therapies that are useful fortreating various mental illnesses and obesity.

BRIEF DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to improved compositions andmethods for the treatment or prevention of various forms of depressionand/or mood disorders, including, for example, breakthrough depressionand treatment-refractory depression, and other mood disorders as well asother ADHD, Parkinson's disease, and obesity, among others.

In one aspect, the present invention provides a method of preventing ortreating breakthrough depression in a patient in need thereof comprisingadministering an effective amount of low dose naltrexone or relatedopioid antagonist.

In another aspect, the present invention provides a method of preventingor treating treatment-refractory depression in a patient in need thereofcomprising administering an effective amount of low dose naltrexone orrelated opioid antagonist.

In a further aspect, the present invention provides a method ofpreventing or treating breakthrough depression in a patient in needthereof comprising administering an effective amount of low dosenaltrexone or related opioid antagonist in combination with an effectiveamount of one or more of a dopamine active anti-depressant agent, adopamine active augmenting agent, a serotonin-norepinephrine reuptakeinhibitor (SNRI), and a selective serotonin re-uptake inhibitor (SSRI).

In another aspect, the present invention provides a method of preventingor treating treatment-refractory depression in a patient in need thereofcomprising administering an effective amount of low dose naltrexone orrelated opioid antagonist in combination with an effective amount of oneor more of a dopamine active anti-depressant agent, a dopamine activeaugmenting agent, a serotonin-norepinephrine reuptake inhibitor (SNRI),and a selective serotonin re-uptake inhibitor (SSRI).

In another aspect, the present invention provides a method of preventingor treating one or more of depression, Parkinson's disease, attentiondeficit disorder (ADHD). Restless Leg Syndrome (RLS), and obesitycomprising administering an effective amount of low dose naltrexone orrelated opioid antagonist in combination with an effective amount ofanother agent described herein.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs.

DESCRIPTION OF THE FIGURES

FIGS. 1A and 1B show patient response during clinical testing of lowdose naltrexone treatment for depression as measured by 17-item HamiltonRating Scale for Depression (HAM-D-17) over three weeks (FIG. 1A) andsix weeks (FIG. 1B), respectively.

FIGS. 2A and 2B show patient response during clinical testing of lowdose naltrexone treatment for depression as measured by 28-item HamiltonRating Scale for Depression (HAM-D-28) over three weeks (FIG. 2A) andsix weeks (FIG. 2B), respectively.

FIGS. 3A and 3B show patient response during clinical testing of lowdose naltrexone treatment for depression as measured by 10-itemMontgomery-Asberg Depression Rating Scale (MADRS-10) over three weeks(FIG. 3A) and six weeks (FIG. 3B), respectively.

FIGS. 4A and 4B show patient response during clinical testing of lowdose naltrexone treatment for depression as measured by 15-itemMontgomery-Asberg Depression Rating Scale (MADRS-15) over three weeks(FIG. 4A) and six weeks (FIG. 4B), respectively.

FIGS. 5A and 5B show patient response during clinical testing of lowdose naltrexone treatment for depression as measured by Clinical GlobalImpressions—Severity (CGI-S) over three weeks (FIG. 5A) and six weeks(FIG. 5B), respectively.

FIGS. 6A and 6B show patient response during clinical testing of lowdose naltrexone treatment for depression as measured by Clinical GlobalImpressions—Improvement (CGI-I) over three weeks (FIG. 6A) and six weeks(FIG. 6B), respectively.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based, in part, on the discovery that low dosenaltrexone is useful in the treatment of various forms of depressionand/or mood disorders, including, for example, breakthrough depressionand treatment-refractory depression, and other mood disorders.

In one aspect, the present invention provides a method of preventing ortreating breakthrough depression in a patient in need thereof comprisingadministering an effective amount of low dose naltrexone or relatedopioid antagonist. In one aspect, the present invention provides a useof low dose naltrexone or related opioid antagonist for the preventionor treatment of breakthrough depression.

In another aspect, the present invention provides a method of preventingor treating treatment-refractory depression in a patient in need thereofcomprising administering an effective amount of low dose naltrexone orrelated opioid antagonist. In one aspect, the present invention providesa use of low dose naltrexone or related opioid antagonist for theprevention or treatment of treatment-refractory depression.

In a further aspect, the present invention provides a method ofpreventing or treating breakthrough depression in a patient in needthereof comprising administering an effective amount of low dosenaltrexone or related opioid antagonist in combination with an effectiveamount of one or more of a dopamine active anti-depressant agent, adopamine active augmenting agent, a serotonin-norepinephrine reuptakeinhibitor (SNRI), and a selective serotonin re-uptake inhibitor (SSRI).In one aspect, the present invention provides a use of low dosenaltrexone or related opioid antagonist in combination with an effectiveamount of one or more of a dopamine active anti-depressant agent, adopamine active augmenting agent, a serotonin-norepinephrine reuptakeinhibitor (SNRI), and a selective serotonin re-uptake inhibitor (SSRI)for the prevention or treatment of breakthrough depression.

In another aspect, the present invention provides a method of preventingor treating treatment-refractory depression in a patient in need thereofcomprising administering an effective amount of low dose naltrexone orrelated opioid antagonist in combination with an effective amount of oneor more of a dopamine active anti-depressant agent, a dopamine activeaugmenting agent, a serotonin-norepinephrine reuptake inhibitor (SNRI),and a selective serotonin re-uptake inhibitor (SSRI). In one aspect, thepresent invention provides a use of low dose naltrexone or relatedopioid antagonist in combination with an effective amount of one or moreof a dopamine active anti-depressant agent, a dopamine active augmentingagent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and aselective serotonin re-uptake inhibitor (SSRI) for the prevention ortreatment of treatment-refractory depression.

In another aspect, the present invention provides a method of preventingor treating one or more of depression, Parkinson's disease, bipolardisorder, bipolar mood disorder, attention deficit disorder (ADHD),Restless Leg Syndrome (RLS), and obesity comprising administering aneffective amount of low dose naltrexone or related opioid antagonistoptionally in combination with an effective amount of another agentdescribed herein. In another aspect, the present invention provides ause of low dose naltrexone or related opioid antagonist optionally incombination another agent described herein for the prevention ortreatment of one or more of depression, Parkinson's disease, bipolardisorder, bipolar mood disorder, attention deficit disorder (ADHD),Restless Leg Syndrome (RLS), and obesity.

In one embodiment, the effective amount of low dose naltrexone orrelated opioid antagonist or a combination of an effective amount of lowdose naltrexone or related opioid antagonist in combination with aneffective amount of an agent described herein is administered inconjunction with a patient's pre-existent anti-depression treatment,wherein the pre-existent anti-depression treatment comprises one or moreof a dopamine active anti-depressant agent, a dopamine active augmentingagent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and aselective serotonin re-uptake inhibitor (SSRI). In one embodiment, thepresently described methods of treatment involve the administration ofan effective amount of low dose naltrexone or related opioid antagonistin combination with an effective amount of an agent described herein. Inone embodiment, the presently described methods of treatment involve theadministration of an effective amount of low dose naltrexone or relatedopioid antagonist to a patient undergoing treatment with an effectiveamount of an agent described herein. In some embodiments, the effectiveamount of low dose naltrexone or related opioid antagonist is anadjuvant therapy to another agent described herein.

In another embodiment, the breakthrough depression comprises depressiverelapse and/or recurrence.

In still another embodiment, the low dose naltrexone or related opioidantagonist is administered at doses that reverse or preventdesensitization of a dopamine receptor, including, for example, the D₂and D₃ receptors. In still another embodiment, the low dose naltrexoneor related opioid antagonist is administered at doses that do not effectopioid receptors. In still another embodiment, the low dose naltrexoneor related opioid antagonist is administered at doses that aresubstantially below levels that induce significant opioid blockade.Substantially below refers to levels are less than about 50%, or about40%, or about 30%, or about 20%, or about 10%, or about 5%, or about 2%,or about 1% of levels that induce significant opioid blockade. In oneembodiment, the amount of naltrexone or related opioid antagonistadministered is less than 10 mg, or about 1 to about 4 mg, or about 1mg.

In another embodiment, the dopamine active anti-depressant agent is oneor more of bupropion, aripiprazole, and sertraline. In some embodiments,aripiprazole is not an anti-depressant agent per se. In anotherembodiment, the SNRI is selected from duloxetine, venlafaxine,nefazodone, and milnacipran. In another embodiment, the dopamine activeaugmenting agent is one or more of an amphetamine salt, pramipexole, andropinirole. In another embodiment, the SSRI is selected from citalopram,dapoxetine, s-citalopram, fluoxetine, fluvoxamine, indalpine,paroxetine, and zimelidine.

In various embodiments, the preventing or treating of depression,including, breakthrough depression and/or treatment-refractorydepression, comprises reduction in length of a depressive episode. Invarious embodiments, the preventing or treating of depression,including, breakthrough depression and/or treatment-refractorydepression, comprises recovery of an anti-depressive effect of thepatient's pre-existent anti-depression treatment regimen. In still othervarious embodiments, the preventing or treating of depression,including, breakthrough depression and/or treatment-refractorydepression, comprises a reduction in the rate of relapse after majordepressive episodes. In further various embodiments, the preventing ortreating of depression, including, breakthrough depression and/ortreatment-refractory depression, comprises prevention or reversal ofloss of efficacy of the patient's pre-existent anti-depressiontreatment. In various embodiments, the preventing or treating ofdepression, including, breakthrough depression and/ortreatment-refractory depression, comprises reduction in an effectivedosage of the patient's pre-existent anti-depression treatment, whichmay, for example, causes one or more of a reduction in side effects andincrease in patient adherence. In some embodiments, the depression beingtreated is bipolar depression. Including, for example, treatmentresistant bipolar depression.

In another embodiment, the effective amount of low dose naltrexone orrelated opioid antagonist or a combination regimen comprising naltrexoneor related opioid antagonist is administered orally or subcutaneously.

In still another embodiment, the naltrexone or related opioid antagonistand one or more of a dopamine active anti-depressant agent, a dopamineactive augmenting agent, a serotonin-norepinephrine reuptake inhibitor(SNRI), and a selective serotonin re-uptake inhibitor (SSRI) areco-formulated in a single dosage form. In various embodiments, thedosage form is an oral dosage form or a subcutaneous dosage form.

In still another embodiment, an outcome of the methods of the presentinvention is rapid antidepressant response (e.g. less than about 10days) compared to the usual latency for response to traditionalantidepressant pharmacotherapy (about 3-6 weeks).

As used herein, “a,” “an,” or “the” can mean one or more than one.

Further, the term “about” when used in connection with a referencednumeric indication means the referenced numeric indication plus or minusup to 10% of that referenced numeric indication. For example, thelanguage “about 50” covers the range of 45 to 55.

An “effective amount” of a “therapeutically effective amount,” when usedin connection with medical uses is an amount that is effective forproviding a measurable treatment, prevention, or reduction in the rateof pathogenesis of a disease of interest.

Effective amounts, toxicity, and therapeutic efficacy can be determinedby standard pharmaceutical procedures in, for example, cell cultures orexperimental animals, e.g., for determining the LD50 (the dose lethal toabout 50% of the population) and the ED50 (the dose therapeuticallyeffective in about 50% of the population). The dosage can vary dependingupon the dosage form employed and the route of administration utilized.The dose ratio between toxic and therapeutic effects is the therapeuticindex and can be expressed as the ratio LD50/ED50. In some embodiments,compositions and methods that exhibit large therapeutic indices areprovided. A therapeutically effective dose can be estimated initiallyfrom in vitro assays, including, for example, cell culture assays. Also,a dose can be formulated in animal models to achieve a circulatingplasma concentration range that includes the IC50 as determined in cellculture, or in an appropriate animal model. Levels of the describedcompositions in plasma can be measured, for example, by high performanceliquid chromatography. The effects of any particular dosage can bemonitored by a suitable bioassay. The dosage can be determined by aphysician and adjusted, as necessary, to suit observed effects of thetreatment.

In certain embodiments, the effect will result in a quantifiable changeof at least about 10%, at least about 20%, at least about 30%, at leastabout 50%, at least about 70%, or at least about 90%. In someembodiments, the effect will result in a quantifiable change of about10%, about 20%, about 30%, about 50%, about 70%, or even about 90% ormore. Therapeutic benefit also includes halting or slowing theprogression of the underlying disease or disorder, regardless of whetherimprovement is realized.

In certain embodiments, a pharmacologically effective amount that willtreat the disease recited herein will modulate the symptoms typically byat least about 10%, at least about 20%, at least about 30%, at leastabout 40%, or at least about 50%.

As used herein, something is “decreased” if a read-out of activityand/or effect is reduced by a significant amount, such as by at leastabout 10%, at least about 20%, at least about 30%, at least about 40%,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 90%, at least about 95%, at least about 97%,at least about 98%, or more, up to and including at least about 100%, inthe presence of an agent or stimulus relative to the absence of suchmodulation. As will be understood by one of ordinary skill in the art,in some embodiments, activity is decreased and some downstream read-outswill decrease but others can increase.

Conversely, activity is “increased” if a read-out of activity and/oreffect is increased by a significant amount, for example by at leastabout 10%, at least about 20%, at least about 30%, at least about 40%,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 90%, at least about 95%, at least about 97%,at least about 98%, or more, up to and including at least about 100% ormore, at least about 2-fold, at least about 3-fold, at least about4-fold, at least about 5-fold, at least about 6-fold, at least about7-fold, at least about 8-fold, at least about 9-fold, at least about10-fold, at least about 50-fold, at least about 100-fold, in thepresence of an agent or stimulus, relative to the absence of such agentor stimulus.

As referred to herein, all compositional percentages are by weight ofthe total composition, unless otherwise specified. As used herein, theword “include,” and its variants, is intended to be non-limiting, suchthat recitation of items in a list is not to the exclusion of other likeitems that may also be useful in the compositions and methods of thistechnology. Similarly, the terms “can” and “may” and their variants areintended to be non-limiting, such that recitation that an embodiment canor may comprise certain elements or features does not exclude otherembodiments of the present technology that do not contain those elementsor features.

Although the open-ended term “comprising,” as a synonym of terms such asincluding, containing, or having, is used herein to describe and claimthe invention, the present invention, or embodiments thereof, mayalternatively be described using alternative terms such as “consistingof” or “consisting essentially of.”

In various aspects, the present invention pertains to various forms ofdepression and other mood disorders. Diagnosis of depressive conditionsmay be informed by criteria found in the American PsychiatricAssociation's revised fourth edition of the Diagnostic and StatisticalManual of Mental Disorders (DSM-IV-TR), and the World HealthOrganization's International Statistical Classification of Diseases andRelated Health Problems (ICD-10). Generally, depressive episode refersto a single episode and recurrent depressive disorder refers to repeatedepisodes. Both DSM-IV-TR and ICD-10 mark out typical depressivesymptoms. ICD-10 defines three typical depressive symptoms, depressedmood, anhedonia, and reduced energy. Two of these should be present todetermine depressive disorder diagnosis. DSM-IV-TR defines two maindepressive symptoms, depressed mood and anhedonia. At least one of thesemust be present to make a diagnosis of a major depressive episode.

Depression encompasses a large variety of disorders, including, but notlimited to, the five further subtypes of major depressive disorder(MDD), i.e. melancholic depression, atypical depression, catatonicdepression, postpartum depression, and seasonal affective disorder. Insome embodiments, the depression is dopamine-receptor relateddepression. In some embodiments, the present depression is not relatedto opioid receptors.

The present invention, in some aspects, pertains to depression and mooddisorders that are described and classified by the DSM codes. These caninclude, for example: major depressive disorder, recurrent—296.36, infull remission—296.35, in partial remission—296.31, mild—296.32,moderate—296.33, severe without psychotic features—296.34, severe withpsychotic features—296.30, unspecified, as well as major depressivedisorder, single episode-296.26, in full remission—296.25, in partialremission—296.21, mild—296.22, moderate-296.23, severe without psychoticfeatures—296.24, severe with psychotic features—296.20, unspecified, aswell as 311 depressive disorder, not otherwise specified (NOS). Further,codes 293.83—mood disorder due to . . . [general medical condition] and296.90—mood disorder NOS, are included.

The present invention includes compositions and methods for thetreatment and/or prevention of the various disorders encompassed in theterm depression, and related mood disorders.

Breakthrough depression is a subset of depression that may be caused bytachyphylaxis or antidepressant tolerance, often called antidepressant“poop-out.” Breakthrough depression is often characterized as acondition in which patients experience a good initial antidepressantresponse which is lost over time with repeated or prolongedantidepressant treatment. This phenomenon is distinct from an initialnon-response or a partial response. In one embodiment, the breakthroughdepression comprises depressive relapse and/or recurrence.

Treatment-resistant depression is a subset of depression that is oftencharacterized as a condition in which optimization of treatment orcomplete remission does not occur. When remission is not achieved, theprobability of relapse is greater. In one embodiment, thetreatment-resistant depression comprises depressive relapse and/orrecurrence.

Further, in some aspects, the present invention comprises treatment ofother disorders individually or in combination with depression asdescribed herein. For example, in some embodiments, the presentinvention includes the treatment of one or more of depression,Parkinson's disease, bipolar disorder, bipolar mood disorder, attentiondeficit disorder (ADHD), Restless Leg Syndrome (RLS), and obesity. Insome embodiments, the present invention is useful for treatment of oneor more of depression, Parkinson's disease, bipolar disorder, bipolarmood disorder, ADHD, RLS, and obesity in the same subject.

In some embodiments, the present invention includes treatment ofParkinson's disease. Parkinson's disease occurs when a group of cells inthe substantia nigra that produce dopamine malfunction and die. When asubject has Parkinson's disease, his or her dopamine-producing cellsbegin to die, and therefore, the amount of dopamine produced in thebrain decreases. Signals from the brain that tell the body how and whento move are therefore delivered more slowly, leaving a subject incapableof initiating and controlling movements in a normal way. Four symptomsof Parkinson's disease are tremor, or trembling in hands, arms, legs,jaw, and face; rigidity, or stiffness of the limbs and trunk;bradykinesia, or slowness of movement; and postural instability, orimpaired balance and coordination. Other symptoms may include depressionand other emotional changes; difficulty in swallowing, chewing, andspeaking; urinary problems or constipation; skin problems; and sleepdisruptions, etc. Accordingly, the methods and compositions of thepresent invention are useful for treatment of Parkinson's disease. Insome embodiments, the present invention is useful for treatment of bothParkinson's disease and depression in the same subject.

In some embodiments, the present compositions and methods are useful inthe treatment of Parkinson's disease and/or depression, including by wayof non-limiting example, breakthrough depression and/ortreatment-refractory depression, associated with and/or caused byParkinson's disease. In some embodiments, the present invention providesa method for treating Parkinson's disease and/or depression, includingby way of non-limiting example, breakthrough depression and/ortreatment-refractory depression, associated with and/or caused byParkinson's disease by administering an effective amount of a low dosenaltrexone to a patient in need thereof. The patient may also receivepre-existent and/or combination therapy that comprises one or more ofthe agents described herein.

In some embodiments, the present invention includes treatment of bipolardisorder and/or bipolar mood disorder. Bipolar disorder is in a class ofmood disorders that is marked by dramatic changes in mood, energy andbehavior. A key characteristic of people with bipolar disorder isalternating between episodes of mania (extreme elevated mood) anddepression (extreme sadness). These episodes can last from hours tomonths. The mood disturbances are severe enough to affect the person'sability to function. The experience of mania can be very frightening andlead to impulsive behavior that has serious consequences for the personand the family. A depressive episode makes it difficult or impossiblefor a person to function in his or her daily life. Symptoms ofdepression include, for example, sad mood; preoccupation with failuresor inadequacies; loss of self-esteem; slowed thinking, forgetfulness;difficulties in concentrating and in making decisions; loss of interestin work, hobbies, people; social isolation; lethargy or agitation;changes in appetite; oversleeping or insomnia; decreased sexual drive;and suicidal thoughts. Symptoms of mania include, for example, elevated,expansive mood; extreme irritability; rapid, unpredictable emotionalchanges; racing thoughts, flights of ideas; overreaction to stimuli;misinterpretation of events; increased interest in activities;overspending; sense of grandiosity, inflated self-esteem; excessiveenergy; decreased need for sleep; increased sexual drive, sexualindiscretions; and poor judgment.

In some embodiments, the present compositions and methods are useful inthe treatment of depression, including by way of non-limiting example,breakthrough depression and/or treatment-refractory depression,associated with and/or caused by bipolar disorder and/or bipolar mooddisorder. In some embodiments, the present invention provides a methodfor treating depression, including by way of non-limiting example,breakthrough depression and/or treatment-refractory depression,associated with and/or caused by bipolar disorder and/or bipolar mooddisorder by administering an effective amount of a low dose naltrexoneto a patient in need thereof. The patient may also receive pre-existentand/or combination therapy that comprises one or more of the agentsdescribed herein. In some embodiments, the pre-existent and/orcombination therapy is bupropion. In various embodiments, depression,including by way of non-limiting example, breakthrough depression and/ortreatment-refractory depression, associated with and/or caused bybipolar disorder and/or bipolar mood disorder is distinct from unipolardepression, including by way of non-limiting example, breakthroughdepression and/or treatment-refractory depression.

In some embodiments, the present invention includes treatment of ADHD.ADHD is a disorder characterized by, for example, inattentiveness,over-activity, impulsivity, or a combination. Decreased phasic dopaminerelease is believed, without wishing to be bound by theory, to be animportant deficit in ADHD. Accordingly, the methods and compositions ofthe present invention are useful for treatment of ADHD. In someembodiments, the present invention is useful for treatment of both ADHDand depression in the same subject.

In the treatment of ADHD, exemplary agents for coformulation include,but are not limited to, a methylphenidate formulation (e.g. in immediateor delayed release form, including selective enantiomers), anamphetamine formulation (e.g. in an immediate or delayed release form,including selective enantiomers), or a norepinephrine transporterinhibitor such as atomoxetine, all of whose actions are believed,without wishing to be bound by theory, to be mediated by augmentation ofextracellular dopamine levels, as well as other drugs enhancingdopaminergic neurotransmission. Typical doses of ADDERALL, anamphetamine preparation, range from a daily dose of 2.5 mg per day up todoses 30 mg given twice a day orally. Typical doses of CONCERTA rangefrom 18 mg/day to 72 mg/day, generally not to exceed 2 mg/kg/day.Typical doses of RITALIN (methylphenidate) tablets are 10 to 60 mg/daygiven twice or three times per day; higher doses have been used. Typicaldoses of atomoxetine are 0.5 mg/kg to 1.4 mg/kg taken twice daily orallyup to a maximum of a 100 mg daily dose. Lower doses may be effective,when co-administered or co-formulated with a low dose of naltrexone,naloxone, or other opioid receptor antagonist. A benefit of low doseopioid antagonists stabilizing dopamine augmentation in treatment ofADHD includes the prevention of dose escalation, therefore allowing useof lower doses of agents such as amphetamine salts and methylphenidate,which would, without wishing to be bound by theory, minimize the knowncardiovascular risks of arrhythmias, hypertension and and/or tachycardialinked to an elevated lifetime probability of myocardial infarction andstroke. In some embodiments, the present methods and formulationspertain to methylphenidate along with d-amphetamine.

In some embodiments, the present invention provides a method fortreating ADHD by administering an effective amount of a low dosenaltrexone to a patient in need thereof. The patient may also receivepre-existent and/or combination therapy that comprises one or more ofthe agents described herein.

In some embodiments, the present invention includes treatment of RLS,also known as Willis-Ekbom disease (WED). RLS is a disorder of the partof the nervous system that affects the legs and causes an urge to movethem. Because it can interfere with sleep, it may be considered a sleepdisorder. RLS is a neurological disorder characterized by anirresistible urge to move one's body to stop uncomfortable or oddsensations. It most commonly affects the legs, but can affect the arms,torso, head, and even phantom limbs. Moving the affected body partmodulates the sensations, providing temporary relief. In someembodiments, the present invention includes treatment or prevention ofRLS comprising administering low dose naltrexone (or other opioidreceptor antagonist), optionally in combination with any of the agentsdescribed herein.

In some embodiments, the present invention provides a method fortreating RLS by administering an effective amount of a low dosenaltrexone to a patient in need thereof. The patient may also receivepre-existent and/or combination therapy that comprises one or more ofthe agents described herein.

In some embodiments, the present invention includes treatment of obesityand metabolic syndrome which may accompany obesity, including, by way ofnon-limiting example, insulin resistance and type II diabetes.Bromocriptine, a dopamimetic, at a dose of 2.5 mg reduces leptin,insulin, and glucose levels in obese female human subjects and improvesglycemic control in type II diabetics. Genetic studies have showngenetic polymorphisms of the dopamine D3 receptor which produce lesserlevels of dopamine D3 signaling are more commonly seen in obese adultsparticularly those with binge eating disorders. Further, imaging studieshave suggested that decreased dopamine D2 signaling in obese subjectsand animal studies have shown that bromocriptine administered to leptindeficient animals reduces hyperphagia and adiposity. In someembodiments, low dose naltrexone (or other opioid receptor antagonist),optionally in combination with any of the agents described herein,including dopamine D2 and D3 agonists and partial agonists including butnot limited to bromocriptine, are useful in the treatment of obesity andmetabolic syndrome which may accompany obesity. Without wishing to bebound by theory, such treatment may enhance the metabolic effects ofsuch dopamimetics by preventing desensitization of dopamine D2 and D3receptors with chronic treatment. In some embodiments, the presentinvention is useful for treatment of both obesity and metabolic syndromewhich may accompany obesity and depression in the same subject.

In some embodiments, the present invention provides a method fortreating obesity and/or metabolic syndrome which may accompany obesity,including, by way of non-limiting example, insulin resistance and typeII diabetes by administering an effective amount of a low dosenaltrexone to a patient in need thereof. The patient may also receivepre-existent and/or combination therapy that comprises one or more ofthe agents described herein. In some embodiments, the present inventionprovides a method for treating binge eating disorder, including moderateto severe binge eating disorder. In various embodiments, the treatmentof binge eating disorder may include a combination therapy of low dosenaltrexone and lisdexamfetamine (e.g. VYVANSE).

Naltrexone(17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) is asmall molecule agent of the following structure:

Naltrexone is a potent, orally bioavailable opioid receptor antagonist.More specifically, without wishing to be bound by theory, naltrexone isa competitive antagonist (possibly exerting inverse agonistic effects)at mu and delta opioid receptors. It has been used clinically in themanagement of alcohol dependence and in the treatment of opioiddependence. In the context of alcohol dependence, naltrexone wasapproved by the U.S. F.D.A. in 1994. Since then a number of studies haveconfirmed its efficacy in reducing frequency and severity of relapse todrinking. The standard regimen is one 50 mg tablet per day, whenadministered orally or 380 mg every 4 weeks (or once a month) viaintramuscular gluteal injection, alternating buttocks for anextended-release injectable suspension (e.g. VIVITROL). In the contextof opioid dependence, naltrexone was approved by the U.S. F.D.A. in1984. Naltrexone may help patients overcome opioid addiction by blockingthe drugs' euphoric effects. The standard regimen is an initial dose of25 mg orally one time and maintenance doses of, if no withdrawal signsoccur, 50 mg orally once a day, or as alternatives (e.g. to improvecompliance): 50 mg orally on week days and 100 mg orally on Saturday; or100 mg orally every other day; or 150 mg orally every third day, whenadministered orally or 380 mg every 4 weeks (or once a month) viaintramuscular gluteal injection, alternating buttocks for anextended-release injectable suspension.

A significant disadvantage of the prescription of an opioid antagonist,such as naltrexone and related opioid antagonists, at a usual dose isthat they render a patient inaccessible to opioid analgesia in emergencysituations. Another major limitation of the usual does of naltrexone andrelated opioid antagonists is that these doses of naltrexone and relatedopioid antagonists or inverse agonists carry a risk of hepatotoxicity.Further, opioid blocking doses of naltrexone and related opioidantagonists, perhaps because of their inverse agonist effect, can createdysphoria and/or possible anhedonia. This could exacerbate depressionand/or promote suicidal ideation (as noted by the FDA in their warningsaccompanying usual doses of naltrexone either p.o. or s.c).

Surprisingly, low dose naltrexone (e.g. less than 10 mg) was found toenhance the effects of opioid agonists. As a possible mechanism ofaction, without wishing to be bound by theory, recent studies determinedthat naltrexone binds to the C-terminal pentapeptide of the scaffoldingprotein filamin A (which is involved in receptor trafficking) withstrong avidity (K_(D) less than 5 pM), which may prevent or reverse achange in G-protein signaling in G coupled receptor systems, such as themu opioid receptor, after prolonged stimulation by agonists (Wang,Frankfurt, & Burns, 2008 PloS One, 3(2), e1554). Filamin A is also foundin Dopamine 2 and 3 receptors.

Accordingly, in some aspects of the invention there are providedcompositions and methods comprising low dose naltrexone or a relatedopioid antagonist that reverse or prevent desensitization to D₂/D₃agonists. Accordingly, in some aspects of the invention there areprovided compositions and methods comprising low dose naltrexone or arelated opioid antagonist that do not effect opioid receptors. Instudies regarding the illness Restless Leg Syndrome (RLS), thought toresult from a deficiency of D₂/D₃ compared to D₁ agonism, and typicallytreated with the D₂/D₃ agonists pramipexole or ropinirole, periodic limbmovements of sleep were measured with Philips Respironics Actigraphydevices, confirming that low dose naltrexone allowed equivalent controlof limb movements at one-half the prior dose of D₂/D₃ agonists (see U.S.Ser. No. 12/603,235, hereby incorporated by reference in its entirety).

Additionally, there have been reported observations that followingsuccessful treatment of depression with SSRIs, a D₂ antagonist broughtreturn of depressive symptoms (Wilner et al., 2005, J. AffectiveDisorders, 86(1), 37-45, the contents of which are hereby incorporatedby reference in its entirety). Analogous observations in an animal modelof depression, reversed by tricyclic antidepressants, suggested thatretention of sensitivity of the D₂ receptor (i.e., preventing itsdesensitization) was essential to effective antidepressant treatmentswith SSRIs or SNRIs (Wilner, 2002 in Di Chiara, G. (Ed.) Handbook ofPhysiology: Dopamine in the CNS. Springer, Berlin, pp. 387-416, thecontents of which are hereby incorporated by reference in its entirety).

Further, in Parkinson's Disease, dopamine D2 and/or D2/3 agonists,monoamine oxidase inhibitors (MAOi), catechol-O-methyl transferaseinhibitors (COMTi), and L-DOPA formulations, either separately ortogether have been shown to be therapeutically efficacious. The dopamineD2 and D2/3 agonists include, but are not limited, to pramipexole,ropinirole, bromocriptine, sumanirole, and pergolide. The side effectsof “wearing off” and “on-off” periods, as well as loss of therapeuticefficacy of these agents, have been reported with these drugs. Withoutwishing to be bound by theory, these effects may be mediated bydesensitization of dopamine D2 and D3 receptors.

Accordingly, in various aspects, the present invention pertains to dosesof naltrexone or related opioid antagonist that reverse or preventdesensitization of a dopamine receptor, including, for example, the D₂and D₃ receptors. In other embodiments, any dopamine receptor of theD₁-like family and/or D₂-like family is the dopamine receptor on whichdoses of naltrexone or related opioid antagonist reverse or preventdesensitization. In some embodiments, the dopamine receptor is any oneof the D₁, D₂, D₃, D₄, and D₅ receptors. In various aspects, the presentinvention pertains to doses of naltrexone or related opioid antagonistthat are substantially below levels that induce significant opioidblockade.

In various aspects, the present invention also encompasses compositionsand methods of treatment comprising other opioid antagonists related tonaltrexone. These compounds include, by way of non-limiting example,naloxone, diprenorphine, etorphine, dihydroetorphine, and combinationsthereof.

In one embodiment, the amount of naltrexone or related opioid antagonistadministered is less than 10 mg. In another embodiment, amount ofnaltrexone or related opioid antagonist administered is about 9 mg, orabout 8 mg, or about 7 mg, or about 6 mg, or about 5 mg, or about 4 mg,or about 3 mg, or about 2 mg, or about 1 mg. In some embodiments, thedose of naltrexone or related opioid antagonist is less than 1 mg. In aspecific embodiment, the dose of naltrexone or related opioid antagonistis 1 mg. In some embodiments, the amount of naltrexone or related opioidantagonist administered is 1 mg or greater up to and not including 5 mg.In some embodiments, the amount of naltrexone or related opioidantagonist administered is 1 mg or greater, but no greater than 5 mg, orabout 4 mg, or about 3 mg, or about 2 mg. In an illustrative embodiment,the naltrexone or related opioid antagonist is administered orally is 1mg or greater up to and not including 5 mg. In some embodiments, thenaltrexone or related opioid antagonist is not provided for bolusadministration.

In some embodiments, the naltrexone or related opioid antagonist isdosed monthly, or weekly, or daily, or twice daily. In a specificembodiment, the dose is twice daily (i.e. bid).

In various embodiments, the naltrexone or related opioid antagonist isadministered at about 9, or about 8, or about 7, or about 6, or about 5,or about 4, or about 3, or about 2, or about 1 mg bid. In a specificembodiment, the dosing is 1 mg bid.

In various embodiments, the present invention provides for theco-administration and/or co-formulation of low dose naltrexone orrelated opioid antagonist and one or more additional agents. Further, insome embodiments, the invention provides administration of low dosenaltrexone or related opioid antagonist in the context of pre-existenttreatments (e.g. anti-depression treatments) that comprise one or moreadditional agents.

In some embodiments the present invention provides the methods andcompositions that comprise dopamine active anti-depressant agent.

Dopamine active anti-depressant agents include agents that effectdopamine levels.

In some embodiments, the dopamine active anti-depressant agent is one ormore of bupropion, aripiprazole, brexpiprazole, and sertraline.

Bupropion ((±)-2-(tert-Butylamino)-1-(3-chlorophenyl)propan-1-one),without wishing to be bound by theory, may have its primarypharmacological action through norepinephrine-dopamine reuptakeinhibition. It binds selectively to the dopamine transporter, but itsbehavioral effects may be attributed to its inhibition of norepinephrinereuptake. It also may act as a nicotinic acetylcholine receptorantagonist.

Aripiprazole(7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one) and brexpiprazole(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one)),without wishing to be bound by theory, are partial dopamine agonist ofthe second generation class of atypical antipsychotics with additionalantidepressant properties that is used in the treatment ofschizophrenia, bipolar disorder, and clinical depression. It is approvedby the U.S. FDA and EMA for various uses. Without wishing to be bound bytheory, Aripiprazole is a dopamimetic at low doses; for example, below10 mg, or below 9 mg, or below 8 mg, or below 7 mg, or below 6 mg, orbelow 5 mg, or below 4 mg, or below 3 mg, or below 2 mg, or below 1 mg.In some embodiments, the present invention comprises methods oftreatment and compositions comprising low dose naltrexone or relatedopioid antagonist and aripiprazole. In some embodiments, aripiprazolemay be considered to be an anti-depressant agent. In some embodiments,aripiprazole is not an anti-depressant agent.

Sertraline((1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine)is a compound of various mood disorder mechanisms. Without wishing to bebound by theory, it may be a dopamine active antidepressant; forexample, at doses of 150 mg or above (for example, 160, or 170, or 180,or 190, or 200 mg). Without wishing to be bound by theory, it may alsobe an antidepressant of the selective serotonin reuptake inhibitor(SSRI) class. It is approved by the U.S. FDA. In some embodiments, thepresent invention provides methods and compositions comprising doses ofsertraline at doses at which sertraline acts as an inhibitor of dopamineuptake. For example, the present invention encompasses doses ofsertraline of doses of above 150 mg daily or above 200 mg daily or above250 mg daily. In some embodiments, the present invention relates to amethod of treating depression, including by way of non-limiting example,breakthrough depression and/or treatment-refractory depression,comprising administering a therapeutically effective low dose amount ofnaltrexone to a patient receiving doses of sertraline of doses of above150 mg daily. In some embodiments, the present invention relates to amethod of treating depression, including by way of non-limiting example,breakthrough depression and/or treatment-refractory depression,comprising administering a therapeutically effective low dose amount ofnaltrexone to a patient receiving doses of sertraline of doses of above150 mg daily as a combination therapy. In some embodiments, thetherapeutically effective low dose amount of naltrexone is 1 mg,optionally bid.

In some embodiments, the present invention provides methods andcompositions that comprise serotonin-norepinephrine reuptake inhibitors(SNRIs).

SNRIs include agents which act upon, and increase, the levels of theneurotransmitters serotonin and norepinephrine, which play an importantrole in mood.

In some embodiments, the SNRI is one or more of duloxetine((+)-(S)-N-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine),venlafaxine((RS)-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol),nefazodone(1-(3-[4-(3-chlorophenyl)piperazin-1-yl]propyl)-3-ethyl-4-(2-phenoxyethyl)-1H-1,2,4-triazol-5(4H)-one), and milnacipran((1R*,2S*)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide).These agents are approved by the U.S. FDA for various uses. For example,the present invention encompasses doses of duloxetine of doses of above60 mg daily or above 80 mg daily or above 100 mg daily. In someembodiments, the present invention relates to a method of treatingdepression, including by way of non-limiting example, breakthroughdepression and/or treatment-refractory depression, comprisingadministering a therapeutically effective low dose amount of naltrexoneto a patient receiving doses of duloxetine of doses of above 80 mgdaily. In some embodiments, the present invention relates to a method oftreating depression, including by way of non-limiting example,breakthrough depression and/or treatment-refractory depression,comprising administering a therapeutically effective low dose amount ofnaltrexone to a patient receiving doses of duloxetine of doses of above80 mg daily as a combination therapy. In some embodiments, thetherapeutically effective low dose amount of naltrexone is 1 mg bid.

Further, SNRIs are also provided in certain embodiments, including, forexample, desvenlafaxine, tramadol, and sibutramine.

In some embodiments the present invention provides the methods andcompositions that comprise dopamine active augmenting agents.

In some embodiments dopamine active augmenting agents include agentsthat may be used in the treatment of depression or other mood disordersand which have been shown to boost the antidepressant effect of a mainantidepressant treatment.

In some embodiments, the dopamine active augmenting agent is one or moreof an amphetamine salt, pramipexole, and ropinirole.

Amphetamine salts include, for example, ADDERALL, a combination of fouramphetamine salts (racemic amphetamine aspartate monohydrate, racemicamphetamine sulfate, dextroamphetamine saccharide, and dextroamphetaminesulfate). ADDERALL, without wishing to be bound by theory, is a dopaminereleasing agent, a norepinephrine releasing agent, and can be mildlyserotonergic.

Pramipexole((S)-N⁶-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine)),without wishing to be bound by theory, is a dopamine agonist of thenon-ergoline class.

Ropinirole (4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one)),without wishing to be bound by theory, is also a dopamine agonist of thenon-ergoline class of medications.

In some embodiments, the present invention provides the methods andcompositions that comprise selective serotonin re-uptake inhibitors(SSRIs).

SSRIs include agents which act upon, and increase, the levels of theneurotransmitter serotonin, which plays an important role in mood.

In some embodiments, the SSRI is one or more of citalopram((RS)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile),Dapoxetine(S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine),S-Citalopram((S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile),Fluoxetine((RS)-N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine),Fluvoxamine ((E)-5-methoxy-1-[4-(trifluoromethyl)phenyl]pentan-1-oneO-2-aminoethyl oxime), Indalpine (3-(2-piperidin-4-ylethyl)-1H-indole),Paroxetine((3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine),and Zimelidine((Z)-3-(4-bromophenyl)-N,N-dimethyl-3-(pyridin-3-yl)prop-2-en-1-amine).

Further SSRIs are also provided in certain embodiments, including, forexample, citalopram, escitalopram, paroxetine, fluoxetine, andfluvoxamine.

In various other embodiments, the invention provides further agents thatmay be used in the methods and compositions described herein.

For example, in some embodiments, further agents may include serotoninantagonist and reuptake inhibitors (SARIs), such as, for example,etoperidone, lubazodone, nefazodone, and trazodone.

In other embodiments further agents may include norepinephrine reuptakeinhibitors (NRIs), such as, for example, atomoxetine, reboxetine, andviloxazine.

In still other embodiments, further agents may includenorepinephrine-dopamine reuptake inhibitors (NDRIs), such as, forexample, bupropion, dexmethylphenidate, methylphenidate, andmethylphenidate. In some embodiments, the present invention comprisesmethods of treatment and compositions comprising low dose naltrexone orrelated opioid antagonist and methylphenidate.

In other embodiments, further agents may include norepinephrine-dopaminereleasing agents (NDRAs), such as, for example, amphetamine, variousamphetamine salts (e.g. salts of racemic amphetamine anddextroamphetamin, Adderall, dextroamphetamine, dextromethamphetamine,lysine-amphetamine (e.g. Vyvanase) and lisdexamfetamine. In someembodiments, the present invention comprises methods of treatment andcompositions comprising low dose naltrexone or related opioid antagonistand amphetamines.

In yet another embodiment, further agents may include tricyclicantidepressants (TCAs), such as, for example, amitriptyline,butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine,iprindole, lofepramine, melitracen, nortriptyline, opipramol,protriptyline, and trimipramine.

In yet another embodiment, further agents may include tetracyclicantidepressants (TeCAs), such as, for example, amoxapine, maprotiline,mianseri, and mirtazapine.

In other embodiments, further agents may include monoamine oxidaseinhibitors (MAOIs), such as, for example, isocarboxazid, moclobemide,phenelzine, pirlindole, selegiline, and tranylcypromine.

In other embodiments further agents may include 5-HT_(1A) receptorpartial agonists, such as, for example, buspirone, tandospirone,aripiprazole, vilazodone, and quetiapine.

In still other embodiments further agents may include 5-HT₂ receptorpartial agonists, such as, for example, aripiprazole.

In yet another embodiment, further agents may include 5-HT₂ receptorantagonists, such as, for example, agomelatine, nefazodone, quetiapine,and trimipramine.

In other embodiments further agents may include 5-HT₇ receptorantagonists, such as, for example, aripiprazole and quetiapine.

In other embodiments further agents may include D₂ receptor partialagonists, such as, for example, aripiprazole.

In still other embodiments further agents may include D₂ receptorantagonists, such as, for example, quetiapine.

In other embodiments further agents may include D₃ receptor antagonists,such as, for example, aripiprazole.

In other embodiments further agents may include D₄ receptor antagonists,such as, for example, aripiprazole.

In other embodiments agents may include α-adrenergic receptorantagonists, such as, for example, aripiprazole, mirtazepine, andquetiapine. Mirtazapine (REMERON, AVANZA, ZISPIN) is a noradrenergic andspecific serotonergic antidepressant (NaSSA) useful for the treatment ofdepression. It may be classified, without wishing to be bound by theory,as a centrally acting α₂-adrenergic receptor antagonist. In someembodiments, the present invention comprises methods of treatment andcompositions comprising low dose naltrexone or related opioid antagonistand mirtazepine.

In other embodiments agents may include mACh receptor antagonists, suchas, for example, aripiprazole and quetiapine.

In other embodiments further agents may include serotonin reuptakeinhibitors (SRIs), such as, for example, aripiprazole and vilazodone.

In other embodiments further agents may include norepinephrine reuptakeinhibitors (NRIs), such as, for example, quetiapine.

In still other embodiments further agents may include selectiveserotonin reuptake enhancers (SSREs), such as, for example, tianeptine.

In other embodiments further agents may include sigma receptor agonists,such as, for example, opipramol.

In other embodiments further agents may include mood stabilizers, suchas, for example, amisulpride, asenapine, carbamazepine, lamotrigine,lithium, olanzapine/fluoxetine, and valproic acid.

In some embodiments the present invention provides the methods andcompositions that comprise triple reuptake inhibitors, e.g., dopamine,serotonin and norepinephrine.

In some embodiments, the amount of the compounds described herein ortheir pharmaceutically acceptable salts are admixed with the carriermaterials to produce a single dosage that can vary depending upon thesubject being treated and the particular mode of administration. Invitro or in vivo assays can be employed to help identify optimal dosageranges as well as consultation with teachings that are known in the art.

The dosage of the compounds that can be used with naltrexone or relatedopioid antagonist (for example, as a co-administration and/orco-formulation or as a pre-existent anti-depression treatment) candepend on several factors including the severity of the condition,whether the condition is to be treated or prevented, and the age,weight, and health of the subject to be treated. Additionally,pharmacogenomic (the effect of genotype on the pharmacokinetic,pharmacodynamic or efficacy profile of a therapeutic) information abouta particular subject may affect dosage used. Furthermore, the exactindividual dosages can be adjusted somewhat depending on a variety offactors, including the specific combination of the compounds beingadministered, the time of administration, the route of administration,the nature of the formulation, the rate of excretion, the particulardepression and/or mood disease being treated and the severity of thedisorder. Some variations in the dosage can be expected.

In some embodiments, when orally administered to a mammal, the dosage ofthe compounds to be given with naltrexone or related opioid antagonist(for example, as a co-administration and/or co-formulation or as apre-existent anti-depression treatment) may be 0.001 mg/kg/day to 100mg/kg/day, 0.01 mg/kg/day to 50 mg/kg/day, or 0.1 mg/kg/day to 10mg/kg/day. In some embodiments, when orally administered to a human, thedosage of a compound of the invention and/or additional therapeutic maybe 0.001 mg to 1000 mg per day, 1 mg to 600 mg per day, or 5 mg to 30 mgper day.

In some embodiments, when administered by parenteral injection to amammal, the dosage of the compounds to be given with naltrexone orrelated opioid antagonist (for example, as a co-administration and/orco-formulation or as a pre-existent anti-depression treatment) may be0.1 mg to 250 mg per day, 1 mg to 20 mg per day, or 3 mg to 5 mg perday. Injections may be given up to four times daily.

The doses of low dose naltrexone or related agents are described herein.In general, the doses of other agents that are useful are known to thosein the art (for example, those skilled in psychopharmacology). Forexample, doses, of for example agents described herein for combinationuse with low dose naltrexone, may be determined with referencePhysicians' Desk Reference, 66th Edition, PDR Network; 2012 Edition(Dec. 27, 2011), the contents of which are incorporated by reference inits entirety. For example, a suitable dosage may be in a range of about0.1 mg/kg to about 100 mg/kg of body weight of the subject, for example,about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg,about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg,about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 3 mg/kg,about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg,about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg,about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg,about 95 mg/kg, or about 100 mg/kg body weight, inclusive of all valuesand ranges therebetween

In one aspect, the present invention provides a method of preventing ortreating breakthrough depression in a patient in need thereof comprisingadministering an effective amount of low dose naltrexone or relatedopioid antagonist.

In another aspect, the present invention provides a method of preventingor treating treatment-refractory depression in a patient in need thereofcomprising administering an effective amount of low dose naltrexone orrelated opioid antagonist.

In a further aspect, the present invention provides a method ofpreventing or treating breakthrough depression in a patient in needthereof comprising administering an effective amount of low dosenaltrexone or related opioid antagonist in combination with an effectiveamount of one or more of a dopamine active anti-depressant agent, adopamine active augmenting agent, a serotonin-norepinephrine reuptakeinhibitor (SNRI), and a selective serotonin re-uptake inhibitor (SSRI).

In another aspect, the present invention provides a method of preventingor treating treatment-refractory depression in a patient in need thereofcomprising administering an effective amount of low dose naltrexone orrelated opioid antagonist in combination with an effective amount of oneor more of a dopamine active anti-depressant agent, a dopamine activeaugmenting agent, a serotonin-norepinephrine reuptake inhibitor (SNRI),and a selective serotonin re-uptake inhibitor (SSRI).

In various embodiments, the preventing or treating breakthroughdepression and/or treatment-refractory depression comprises reduction inlength of a depressive episode. In various embodiments, the preventingor treating breakthrough depression and/or treatment-refractorydepression comprises recovery of an anti-depressive effect of thepatient's pre-existent anti-depression treatment regimen. In still othervarious embodiments, the preventing or treating breakthrough depressionand/or treatment-refractory depression comprises a reduction in the rateof relapse after major depressive episodes. In further variousembodiments, the preventing or treating breakthrough depression and/ortreatment-refractory depression comprises prevention or reversal of lossof efficacy of the patient's pre-existent anti-depression treatment. Invarious embodiments, the preventing or treating breakthrough depressionand/or treatment-refractory depression comprises reduction in aneffective dosage of the patient's pre-existent anti-depressiontreatment, which may, for example, causes one or more of a reduction inside effects and an increase in patient adherence.

The efficacy of treating depression (e.g., breakthrough depressionand/or treatment-resistant or treatment-refractory depression) usingmethods and compositions of the present invention may be assessed byvarious methods. For example, information about grading of clinicaleffect can be found in Cusin, Yang, Yeung, and Fava, Rating Scales forDepression (Chapter 2) in Handbook of Clinical Rating Scales andAssessment in Psychiatry and Mental Health (Humana, 2010), Baer andBlias, eds., the contents of which are hereby incorporated by referencein their entirety.

In some embodiments, efficacy of treatment on depression is assessed bythe Hamilton Rating Scale for Depression, for example, a 17-item or28-item Hamilton Rating Scale for Depression (HAM-D-17 or HAM-D-28). Inan embodiment, efficacy may be demonstrated by a reduction in HAM-D-17score of at least about 50%, about 55%, about 60%, about 65%, about 70%,about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%,which signify improved response to treatment. Alternatively, efficacymay be demonstrated by a HAM-D-17 score of less than about 15, about 14,about 13, about 12, about 11, about 10, about 9, about 8, about 7.5,about 7, about 6.5, about 6, about 5.5, about 5, about 4.5, about 4,about 3.5, about 3, about 2.5, about 2, about 1.5, about 1, whichsignify increased remission following treatment. In some embodiments,the pre-treatment patient has a HAM-D-17 score of greater than about 23,or between about 19-23, or between about 14-18, or between about 8-13.In some embodiments. In some embodiments, the HAM-D-17 score effect sizebetween patients not receiving low dose naltrexone or related opioidantagonist and patients receiving low dose naltrexone or related opioidantagonist is about 30, or about 25, or about 20, or about 15, or about14, or about 13, or about 12, or about 11, or about 10, or about 9, orabout 8, or about 7, or about 6, or about 5. In some embodiments, theHAM-D-17 score effect size between patients not receiving low dosenaltrexone or related opioid antagonist and patients receiving low dosenaltrexone or related opioid antagonist is between about 5 to about 15or about 5 to about 10. In some embodiments, the low dose naltrexone orrelated opioid antagonist causes any of the above reductions in HAM-D-17score within about 7 days, or about 10 days, or about 14 days frominitiation of treatment with low dose naltrexone or related opioidantagonist. In some embodiments, any of the above reductions in HAM-D-17score mediated by the low dose naltrexone or related opioid antagonistis durably maintained in the patient (e.g. for about, or greater thanabout, 3 weeks, or about, or greater than about, 1 month, or about, orgreater than about, 2 months, or about, or greater than about, 3 months,or about, or greater than about, 6 months, or about, or greater thanabout, 1 year). In an embodiment, efficacy may be demonstrated by areduction in HAM-D-28 score of at least about 50%, about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about95%, or about 100%, which signify improved response to treatment.Alternatively, efficacy may be demonstrated by a HAM-D-28 score of lessthan about 15, about 14, about 13, about 12, about 11, about 10, about9, about 8, about 7.5, about 7, about 6.5, about 6, about 5.5, about 5,about 4.5, about 4, about 3.5, about 3, about 2.5, about 2, about 1.5,about 1, which signify increased remission following treatment. In someembodiments, the pre-treatment patient has a HAM-D-28 score of greaterthan about 23, or between about 19-23, or between about 14-18, orbetween about 8-13. In some embodiments. In some embodiments, theHAM-D-28 score effect size between patients not receiving low dosenaltrexone or related opioid antagonist and patients receiving low dosenaltrexone or related opioid antagonist is about 30, or about 25, orabout 20, or about 15, or about 14, or about 13, or about 12, or about11, or about 10, or about 9, or about 8, or about 7, or about 6, orabout 5. In some embodiments, the HAM-D-28 score effect size betweenpatients not receiving low dose naltrexone or related opioid antagonistand patients receiving low dose naltrexone or related opioid antagonistis between about 5 to about 15 or about 5 to about 10. In someembodiments, the low dose naltrexone or related opioid antagonist causesany of the above reductions in HAM-D-28 score within about 7 days, orabout 10 days, or about 14 days from initiation of treatment with lowdose naltrexone or related opioid antagonist. In some embodiments, anyof the above reductions in HAM-D-28 score mediated by the low dosenaltrexone or related opioid antagonist is durably maintained in thepatient (e.g. for about, or greater than about, 3 weeks, or about, orgreater than about, 1 month, or about, or greater than about, 2 months,or about, or greater than about, 3 months, or about, or greater thanabout, 6 months, or about, or greater than about, 1 year).

In some embodiments, efficacy of treatment on depression is assessed bythe Montgomery-Asberg Depression Rating Scale, for example, a 10-item or15-item Hamilton Rating Scale for Depression (MADRS-10 or MADRS-15). Inan embodiment, efficacy may be demonstrated by a reduction in MADRS-10score of at least about 50%, about 55%, about 60%, about 65%, about 70%,about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%,which signify improved response to treatment. Alternatively, efficacymay be demonstrated by a MADRS-10 score of less than about 15, about 14,about 13, about 12, about 11, about 10, about 9, about 8, about 7.5,about 7, about 6.5, about 6, about 5.5, about 5, about 4.5, about 4,about 3.5, about 3, about 2.5, about 2, about 1.5, about 1, whichsignify increased remission following treatment. In some embodiments,the pre-treatment patient has a MADRS-10 score of greater than about 34,or between about 20-34, or between about 7-19. In some embodiments. Insome embodiments, the MADRS-10 score effect size between patients notreceiving low dose naltrexone or related opioid antagonist and patientsreceiving low dose naltrexone or related opioid antagonist is about 40,or about 35, or about 30, or about 25, or about 20, or about 15, orabout 14, or about 13, or about 12, or about 11, or about 10, or about9, or about 8, or about 7, or about 6, or about 5. In some embodiments,the MADRS-10 score effect size between patients not receiving low dosenaltrexone or related opioid antagonist and patients receiving low dosenaltrexone or related opioid antagonist is between about 5 to about 15or about 5 to about 10. In some embodiments, the low dose naltrexone orrelated opioid antagonist causes any of the above reductions in MADRS-10score within about 7 days, or about 10 days, or about 14 days frominitiation of treatment with low dose naltrexone or related opioidantagonist. In some embodiments, any of the above reductions in MADRS-10score mediated by the low dose naltrexone or related opioid antagonistis durably maintained in the patient (e.g. for about, or greater thanabout, 3 weeks, or about, or greater than about, 1 month, or about, orgreater than about, 2 months, or about, or greater than about, 3 months,or about, or greater than about, 6 months, or about, or greater thanabout, 1 year).

In an embodiment, efficacy may be demonstrated by a reduction inMADRS-15 score of at least about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, orabout 100%, which signify improved response to treatment. Alternatively,efficacy may be demonstrated by a MADRS-15 score of less than about 15,about 14, about 13, about 12, about 11, about 10, about 9, about 8,about 7.5, about 7, about 6.5, about 6, about 5.5, about 5, about 4.5,about 4, about 3.5, about 3, about 2.5, about 2, about 1.5, about 1,which signify increased remission following treatment. In someembodiments, the pre-treatment patient has a MADRS-15 score of greaterthan about 34, or between about 20-34, or between about 7-19. In someembodiments. In some embodiments, the MADRS-15 score effect size betweenpatients not receiving low dose naltrexone or related opioid antagonistand patients receiving low dose naltrexone or related opioid antagonistis about 40, or about 35, or about 30, or about 25, or about 20, orabout 15, or about 14, or about 13, or about 12, or about 11, or about10, or about 9, or about 8, or about 7, or about 6, or about 5. In someembodiments, the MADRS-15 score effect size between patients notreceiving low dose naltrexone or related opioid antagonist and patientsreceiving low dose naltrexone or related opioid antagonist is betweenabout 5 to about 15 or about 5 to about 10. In some embodiments, the lowdose naltrexone or related opioid antagonist causes any of the abovereductions in MADRS-15 score within about 7 days, or about 10 days, orabout 14 days from initiation of treatment with low dose naltrexone orrelated opioid antagonist. In some embodiments, any of the abovereductions in MADRS-15 score mediated by the low dose naltrexone orrelated opioid antagonist is durably maintained in the patient (e.g. forabout, or greater than about, 3 weeks, or about, or greater than about,1 month, or about, or greater than about, 2 months, or about, or greaterthan about, 3 months, or about, or greater than about, 6 months, orabout, or greater than about, 1 year).

In some embodiments, efficacy of treatment on depression is assessed bythe Clinical Global Impressions—Severity and Improvement (CGI-S andCGI-I) score. In an embodiment, efficacy may be demonstrated by areduction in CGI-S score to about 4, about 3.5, about 3, about 2.5,about 2, about 1.5, about 1, or about 0.5, which signify clinicalresponse. In an embodiment, efficacy may be demonstrated by a reductionin CGI-I score to about 4, about 3.5, about 3, about 2.5, about 2, about1.5, about 1, or about 0.5, which signify clinical response andimprovement. In some embodiments, the pre-treatment patient has a CGI-Sor CGI-I score effect size between patients not receiving low dosenaltrexone or related opioid antagonist and patients receiving low dosenaltrexone or related opioid antagonist is about 1.5, or about 1.3, orabout 1.0, or about 0.7, or about 0.5. In some embodiments, the low dosenaltrexone or related opioid antagonist causes any of the abovereductions in CGI-S or CGI-I score within about 7 days, or about 10days, or about 14 days from initiation of treatment with low dosenaltrexone or related opioid antagonist. In some embodiments, any of theabove reductions in CGI-S or CGI-I score mediated by the low dosenaltrexone or related opioid antagonist is durably maintained in thepatient (e.g. for about, or greater than about, 3 weeks, or about, orgreater than about, 1 month, or about, or greater than about, 2 months,or about, or greater than about, 3 months, or about, or greater thanabout, 6 months, or about, or greater than about, 1 year).

In various aspects, the present invention relates to compositions,pharmaceutical compositions, and formulations comprising naltrexone orrelated opioid antagonist. In various embodiments, the present inventionprovides pharmaceutical compositions, and formulations comprisingnaltrexone or related opioid antagonist and one or more additionalagent. In some embodiments, the additional agent is a compound describedherein. By way of non-limiting example, the additional agent may be adopamine active anti-depressant agent, a dopamine active augmentingagent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and aselective serotonin re-uptake inhibitor (SSRI).

The compounds described herein can possess a sufficiently basicfunctional group, which can react with an inorganic or organic acid, ora carboxyl group, which can react with an inorganic or organic base, toform a pharmaceutically acceptable salt. A pharmaceutically acceptableacid addition salt is formed from a pharmaceutically acceptable acid, asis well known in the art. Such salts include the pharmaceuticallyacceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19(1977) and The Handbook of Pharmaceutical Salts; Properties, Selection,and Use. P. H. Stahl and C. G. Wermuth (eds.), Verlag, Zurich(Switzerland) 2002, which are hereby incorporated by reference in theirentirety.

Pharmaceutically acceptable salts include, by way of non-limitingexample, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide,nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,camphorsulfonate, pamoate, phenylacetate, trifluoroacetate, acrylate,chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, isobutyrate,phenylbutyrate, α-hydroxybutyrate, butyne-1,4-dicarboxylate,hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, glycollate,heptanoate, hippurate, malate, hydroxymaleate, malonate, mandelate,mesylate, nicotinate, phthalate, teraphthalate, propiolate, propionate,phenylpropionate, sebacate, suberate, p-bromobenzenesulfonate,chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate,methylsulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,naphthalene-1,5-sulfonate, xylenesulfonate, and tartarate salts.

The term pharmaceutically acceptable salt also refers to a salt of thecompounds of the present invention having an acidic functional group,such as a carboxylic acid functional group, and a base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such asmono-; bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine,or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl-loweralkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like.

The compositions described herein or their pharmaceutically acceptablesalts which are used in accordance with the present invention mayexhibit stereoisomerism by virtue of the presence of one or moreasymmetric or chiral centers in the compounds. The present inventioncontemplates the various stereoisomers and mixtures thereof. Desiredenantiomers can be obtained by chiral synthesis from commerciallyavailable chiral starting materials by methods well known in the art, ormay be obtained from mixtures of the enantiomers by resolution usingknown techniques.

The compounds described herein or their pharmaceutically acceptablesalts can be administered to a subject in need thereof as a component ofa composition that comprises a pharmaceutically acceptable carrier orvehicle.

The present compositions can optionally comprise a suitable amount of apharmaceutically acceptable excipient so as to provide the form forproper administration to the subject.

Such pharmaceutical excipients can be liquids, such as water and oils,including those of petroleum, animal, vegetable, or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical excipients can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea and the like. In addition,auxiliary, stabilizing, thickening, lubricating, and coloring agents canbe used. In one embodiment, the pharmaceutically acceptable excipientsare sterile when administered to a subject. Water is a useful excipientwhen the compounds of present invention or their pharmaceuticallyacceptable salts are administered intravenously. Saline solutions andaqueous dextrose and glycerol solutions can also be employed as liquidexcipients, specifically for injectable solutions. Suitablepharmaceutical excipients also include starch, glucose, lactose,sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,glycerol monostearate, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. The presentcompositions, if desired, can also comprise minor amounts of wetting oremulsifying agents, or pH buffering agents.

The present compositions and/or additional therapeutics agents can takethe form of solutions, suspensions, emulsions, tablets, pills, pellets,capsules, capsules containing liquids, powders, sustained-releaseformulations, suppositories, emulsions, aerosols, sprays, suspensions,or any other form suitable for use. In one embodiment, the compositionis in the form of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Otherexamples of suitable pharmaceutical excipients are described inRemington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds.,19th ed. 1995), incorporated herein by reference in its entirety.

In one embodiment, the compounds described herein are formulated inaccordance with routine procedures as a composition adapted for oraladministration to human beings. Compositions for oral delivery can be inthe form of tablets (by way of non-limiting example, REVIA), lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups, or elixirs, for example. Orally administered compositions cancomprise one or more agents, for example, sweetening agents such asfructose, aspartame or saccharin; flavoring agents such as peppermint,oil of wintergreen, or cherry; coloring agents; and preserving agents,to provide a pharmaceutically palatable preparation. Moreover, where intablet or pill form, the compositions can be coated to delaydisintegration and absorption in the gastrointestinal tract therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activecompound of the invention are also suitable for oral administration. Inthese latter platforms, fluid from the environment surrounding thecapsule is imbibed by the driving compound, which swells to displace theagent or agent composition through an aperture. These delivery platformscan provide an essentially zero order delivery profile as opposed to thespiked profiles of immediate release formulations. A time-delay materialsuch as glycerol monostearate or glycerol stearate can also be useful.Oral compositions can include standard excipients such as mannitol,lactose, starch, magnesium stearate, sodium saccharin, cellulose, andmagnesium carbonate. In one embodiment, the excipients are ofpharmaceutical grade.

In another embodiment, the compounds described herein or theirpharmaceutically acceptable salts can be formulated for intravenousadministration. Typically, compositions for intravenous administrationcomprise a sterile isotonic aqueous buffer. Where necessary, thecompositions can also include a solubilizing agent. Compositions forintravenous administration can optionally include a local anestheticsuch as lignocaine to lessen pain at the site of the injection.

Generally, the ingredients are supplied either separately or mixedtogether in unit dosage form, for example, as a dry lyophilized-powderor water-free concentrate in a hermetically sealed container such as anampule or sachette indicating the quantity of active agent. Where thecompounds described herein or their pharmaceutically acceptable saltsare to be administered by infusion, they can be dispensed, for example,with an infusion bottle containing sterile pharmaceutical grade water orsaline. Where the compounds described herein or their pharmaceuticallyacceptable salts are administered by injection, an ampule of sterilewater for injection or saline can be provided so that the ingredientscan be mixed prior to administration.

Where the compounds described herein or their pharmaceuticallyacceptable salts can be administered by controlled-release orsustained-release means or by delivery devices that are well known tothose of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of whichis incorporated herein by reference in its entirety. Such dosage formscan be useful for providing controlled- or sustained-release of one ormore active ingredients using, for example, hydropropylmethyl cellulose,other polymer matrices, gels, permeable membranes, osmotic systems,multilayer coatings, microparticles, liposomes, microspheres, or acombination thereof to provide the desired release profile in varyingproportions. Suitable controlled- or sustained-release formulationsknown to those skilled in the art, including those described herein, canbe readily selected for use with the compounds mentioned herein. Theinvention thus provides single unit dosage forms suitable for oraladministration such as, but not limited to, tablets, capsules, gelcaps,and caplets that are adapted for controlled- or sustained-release.

Controlled- or sustained-release of an active ingredient can bestimulated by various conditions, including but not limited to, changesin pH, changes in temperature, concentration or availability of enzymes,concentration or availability of water, or other physiologicalconditions or compounds.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentcompositions can comprise, in one embodiment, from about 0.1% to about99%; and in another embodiment from about 1% to about 70% of thecompounds described herein or their pharmaceutically acceptable salts byweight or volume.

In some embodiments, low dose naltexone or other compounds describedherein may be administered to a subject for a period of about 1, about2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about10, about 11, or about 12 months, or about 2, about 3, about 4, about 5,about 6, about 7, about 8, about 9, about 10 years. In some embodiments,low dose naltexone or other compounds described herein may beadministered to a subject chronically.

In another embodiment, the compounds described herein or theirpharmaceutically acceptable salts act synergistically whenco-administered with another therapeutic agent and are administered atdoses that are lower than the doses commonly employed when such agentsare used as monotherapy. The dosage of compounds described herein ortheir pharmaceutically acceptable salts as well as the dosing schedulecan depend on various parameters, including, but not limited to, thedepression and/or mood disorder being treated, the subject's generalhealth, and the administering physician's discretion. The compoundsdescribed herein or their pharmaceutically acceptable salts, such as,for example, naltrexone or related opioid antagonist, can beadministered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to(e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeksafter) the administration of an additional therapeutic, such as, forexample, one or more of a dopamine active anti-depressant agent, adopamine active augmenting agent, a serotonin-norepinephrine reuptakeinhibitor (SNRI), and a selective serotonin re-uptake inhibitor (SSRI),to a subject in need thereof. In various embodiments, the compoundsdescribed herein or their pharmaceutically acceptable salts areadministered 1 minute apart, 10 minutes apart, 30 minutes apart, lessthan 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hoursto 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hoursapart, 11 hours to 12 hours apart, no more than 24 hours apart or nomore than 48 hours apart.

Methods of administration include but are not limited to oral,subcutaneous, intradermal, intramuscular (by way of non-limitingexample, intramuscular depot, such as, for instance, as described inU.S. Pat. No. 6,569,449, the contents of which are hereby incorporatedby reference in its entirety), intraperitoneal, intravenous, intranasal,epidural, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes, or skin. The mode of administration can be left to thediscretion of the practitioner. In most instances, administrationresults in the release of the compounds described herein or theirpharmaceutically acceptable salts into the bloodstream.

The compounds described herein or their pharmaceutically acceptablesalts can be administered orally. The compounds described herein ortheir pharmaceutically acceptable salts can also be administered by anyother convenient route, for example, by intravenous infusion or bolusinjection, by absorption through epithelial or mucocutaneous linings(e.g., oral mucosa, rectal and intestinal mucosa, etc.) and can beadministered together with another biologically active agent.Administration can be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc., and can be used to administer the compounds describedherein or their pharmaceutically acceptable salts.

In yet another embodiment, the compounds described herein or theirpharmaceutically acceptable salts can be delivered in a controlledrelease system. In one embodiment, a pump may be used (see Langer, 1990,Science 249:1527-1533; Sefton, 1987, CRC Crit. Ref Biomed. Eng. 14:201;Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J.Med. 321:574). In another embodiment, polymeric materials can be used(see Medical Applications of Controlled Release, Langer and Wise (eds.),CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability,Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NewYork (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol.Chem. 23:61; see also Levy et al., 1985, Science 228:190; During et al.,1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105).Other controlled-release systems discussed in the review by Langer,1990, Science 249:1527-1533) may be used.

Administration of the described compounds or their pharmaceuticallyacceptable salts can, independently, be one to four times daily or oneto four times per month or one to six times per year or once every two,three, four or five years. Administration can be for the duration of oneday or one month, two months, three months, six months, one year, twoyears, three years, and may even be for the life of the subject.Chronic, long-term administration will be indicated in many cases. Thedosage may be administered as a single dose or divided into multipledoses.

The dosage regimen utilizing the described compounds or theirpharmaceutically acceptable salts can be selected in accordance with avariety of factors including type, species, age, weight, sex and medicalcondition of the subject; the severity of the condition to be treated;the route of administration; the renal or hepatic function of thesubject; and the specific compound of the invention employed. Thedescribed compounds or their pharmaceutically acceptable salts can beadministered in a single daily dose, or the total daily dosage can beadministered in divided doses of two, three or four times daily. Thecompounds described herein or their pharmaceutically acceptable saltsand/or additional therapeutic can be assayed in vitro or in vivo for thedesired therapeutic or prophylactic activity prior to use in humans.Animal model systems can be used to demonstrate safety and efficacy.

The term subject, as used herein unless otherwise defined, is a mammal,e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, ornon-human primate, such as a monkey, chimpanzee, or baboon. The terms“subject” and “patient” are used interchangeably. In some embodiments, asubject is a human suffering from a type of depression described hereinwho does not also suffer from alcohol or drug dependence.

In one embodiment, the subject is a human. In some embodiments, thehuman is a pediatric human. In other embodiments, the subject is anadult human.

In certain embodiments, the human has an age in a range of from about 0months to about 6 months old, from about 6 to about 12 months old, fromabout 6 to about 18 months old, from about 18 to about 36 months old,from about 1 to about 5 years old, from about 5 to about 10 years old,from about 10 to about 15 years old, from about 15 to about 20 yearsold, from about 20 to about 25 years old, from about 25 to about 30years old, from about 30 to about 35 years old, from about 35 to about40 years old, from about 40 to about 45 years old, from about 45 toabout 50 years old, from about 50 to about 55 years old, from about 55to about 60 years old, from about 60 to about 65 years old, from about65 to about 70 years old, from about 70 to about 75 years old, fromabout 75 to about 80 years old, from about 80 to about 85 years old,from about 85 to about 90 years old, from about 90 to about 95 years oldor from about 95 to about 100 years old.

In addition to treating pre-existing depression and/or mood disordersand/or other disorders descried herein, the described compounds or theirpharmaceutically acceptable salts can be administered prophylacticallyin order to prevent or slow the onset of these disorders. Inprophylactic applications, the described compounds or theirpharmaceutically acceptable salts can be administered to a subjectsusceptible to or otherwise at risk of a particular depression and/ormood disorder and/or other disorders descried herein.

In another embodiment, an outcome of the methods of the presentinvention is rapid antidepressant response as compared to the usuallatency for response to traditional antidepressant pharmacotherapy. Sucha response can be less than about 1 day, or about 2 days, or about 3days, or about 4 days, or about 5 days, or about 6 days, or about 7days, or about 10 days, or about 2 weeks. In some embodiments, thelatency for response to traditional antidepressant pharmacotherapy isabout 3, or about 4, or about 5, or about, 6 weeks, or about 8, or about10 weeks.

The invention also provides kits that can simplify the administration ofthe described compounds or their pharmaceutically acceptable salts, to asubject.

A typical kit of the invention comprises the described compounds ortheir pharmaceutically acceptable salts, for example, in unit dosageform. In one embodiment, the unit dosage form is a container, which canbe sterile, containing an effective amount of a described compound ortheir pharmaceutically acceptable salts and a pharmaceuticallyacceptable carrier, diluent, excipient, or vehicle. The kit can furthercomprise a label or printed instructions instructing the use ofdescribed compounds or their pharmaceutically acceptable salts to treator prevent depression and/or mood disorders and/or other disordersdescried herein. The kit can also further comprise one or moreadditional therapeutic agents, for example, in unit dosage form, such asa container containing an effective amount of the other therapeuticagent. In one embodiment, the kit comprises a container containing aneffective amount of naltrexone or related opioid antagonist or apharmaceutically acceptable salt thereof and an effective amount ofanother therapeutic agent. Examples of other therapeutic agents include,but are not limited to, those listed herein.

This invention is further illustrated by the following non-limitingexamples.

EXAMPLES Example 1: Patient Responses to Low Dose Naltrexone Treatmentof Depression

Patient #1: A middle aged female suffered severe depression withrecurrent major depressive episodes. She had responded briefly tocomplex polypharmacy and electroconvulsive therapy, but depressionusually returned within 3 weeks of these interventions. In addition torestarting aripiprazole (ABILIFY), to which she had transientlyresponded in the past, the patient was instructed to pulverize a tabletof naltrexone 50 mg, and take the smallest fragment with water. A sampleof these fragments was later weighed, indicating she was taking on theaverage about 1 mg of naltrexone daily. The former pharmacologic regimenwas otherwise unchanged.

About one week after initiating low dose naltrexone, the patientexperienced marked remission. Despite minor variation in mood, she hasmaintained the remission for more than 6 months (continuing to present).She has remained on adjunctive naltrexone 1 mg daily.

Patient #2: A particularly treatment-resistant patient with a depressiverecurrence, was administered approximately 1 mg daily of naltrexone to acomplex antidepressant regimen, which included duloxetine and riluzole.This patient demonstrated a robust response within 2 weeks, which hasnow been maintained for over 2 years.

Patient #3: A female patient in her 50s presented withtreatment-resistant depression. The patient was also diagnosed withAttention Deficit Disorder. The patient initially was treated withs-citalopram 15 mg, augmented by dextro-amphetamine. She respondedbriefly but rapidly returned to depressed mood with attention deficits.When naltrexone 1 mg was added to her treatment regime, the patientexperienced a marked lifting of mood, noting that her attention was alsomuch improved. This response was seen within days of the addition ofnaltrexone. She reported no adverse effects.

Patient #4: A 62-year-old female patient weighing approximately 60 kghad suffered severe unremitting depression. She was treated with andresponded to electro-convulsive therapy, but regressed within a week.Complex pharmacotherapy, including s-citalopram augmented byaripiprazole and mirtazepine, led to only transient response, withdepressive symptoms returning after several days. Subsequently, thepatient was prescribed 5 mg naltrexone daily with continuation ofs-citalopram. The patient has remained euthymic during more than twomonths of observation.

Patient #5: A female patient in her 40s had suffered severetreatment-resistant depression, exhibiting low energy, crying, unable toobtain and maintain employment, and anhedonia. She was being treatedwith buproprion XL 300 mg, augmented with melatonin 3 mg andN-acetyl-cysteine 1200 mg. The patient was then co-administerednaltrexone 1 mg, and within two weeks, she experienced marked remission.After five months and continuing, she is no longer crying has improvedmotivation and interests, and has obtained meaningful employment.

Patient #6: A male patient in his 80s with multiple major depressionepisodes, anhedonia, apathy, low energy and poor sleep was being treatedwith duloxetine 60 mg and buproprion 75 mg, and mirtazpine 15 mg.Naltrexone 1 mg was added, and within one week, the patient felt muchbetter, stating that adding the naltrexone has a unique effect. Thepatient also reported that he had more energy, was sleeping better, wassexually active, and had returning interest in his hobby.

Patient #7: A female patient in her late 50s with a brain tumor,epilepsy and somatization disorder, also demonstrated multipledepression episodes. She rarely left her couch, lived in socialisolation, often cried, did not shower or get dressed. She also calledand e-mailed multiple times per day. She was being treated with EffexorXR 75 mg QHS, Xanax 0.5 mg, and Clonazepam 1.5 mg. After addingnaltrexone 1 mg, and gabapentin 300 mg and melatonin 5 mg, within threeweeks, the patient was able to obtain employment, was socializing withfriends, was less anxious. Her crying episodes were replaced withsmiling and laughing.

Patient #8: A treatment-resistant patient with depressive recurrence wasbeing treated with pramipexole with limited benefit. The patient wasthen co-administered 1 mg daily of naltrexone with pramipexole. Thepatient demonstrated a robust response within a few weeks.

Patient #9: A middle-age female suffered severe depression withrecurrent major depressive episodes and social anxiety. She was beingtreated with Adderall 10 mg, levothyroxine 50 mcg, and propranol 10 mg.Naltrexone 1 mg was added to her regimen, and she experiencedimprovement in her depression.

Example 2: Clinical Testing of Low Dose Naltrexone Treatment ofDepression

The clinical studies described herein, in part, assess the magnitude andrate of response to low dose naltrexone, as measured by change on theHamilton Rating Scale for Depression (HAM-D-17 or HAM-D-28), compared toplacebo. Additional assessments are based on the Montgomery-AsbergDepression Rating Scale (MADRS-10 or MADRS-15) and Clinical GlobalImpressions—Severity and Improvement (CGI-S and CGI-I).

The trial was conducted over 6 weeks, with double-blind treatment basedon random assignment to low dose naltrexone or placebo. To assesslongevity of response to Low Dose Naltrexone, patients assigned toactive drug were followed for 6 weeks, but the design did not provide acontrasting placebo group beyond 3 weeks.

12 men and women ages 25 to 64 who received antidepressant regimensincluding at least one dopaminergic agent (an NDRI, pramipexole,aripiperazole at less than or equal to 2 mg, amphetamine salt,methylphenidate, or sertraline at 150 mg or greater), had achievedremission for at least 3 months followed by relapse or recurrence, wererecruited. All ethnicities were included.

Inclusion criteria included an age of 18-65; written informed consent;patients meet DSM-IV criteria (by Structured Clinical Interview forDSM-IV SCID-I/P) for MDD, current; Quick Inventory of DepressiveSymptomatology—Self-Rated (QIDS-SR) score of at least 12 at both screenand baseline visits; received treatment with SSRI in combination with adopaminergic agent; or on an antidepressant with a dopaminergicmechanism of action, including SNRIs, MAOIs, TCAs, or bupropion, inadequate doses, achieved remission per ACNP Task Force guidelines (REF)for ≥3 months, currently in relapse or recurrence without dose changefor at least the past 4 weeks, based on meeting DSM-IV criteria for MDD.

Dopaminergic agents here included, for example, classical stimulantsfrom the amphetamine or methylphenidate families; the wakefulnesspromoting agents, modafinil and armodafinil; dopamine agonists (e.g.pramipexole); or bupropion (≥300 mg/day to ensure significant dopaminereuptake inhibition). Additionally, low dose (≤2.5 mg) Abilify, a D2partial agonist, was included as a dopamine agent. Sertraline,classified as an SSRI, had dopamine reuptake inhibiting propertiesbelieved to be relevant at higher doses (≥150 mg) and was thereforeconsidered a dopaminergic agent, as well as allowed as SSRI monotherapyat dopaminergic doses. SNRIs (e.g. venlafaxine) and TCAs (e.g.nortriptyline) were known to have prominent inhibitory effects on thereuptake of norepinephrine; however, since the norepinephrinetransporter was responsible for both norepinephrine and dopaminereuptake in the prefrontal cortex, these agents were also considered tobe pro-dopaminergic antidepressants.

During the baseline visit, patients were on a stable dose ofantidepressant regimen for the past 4 weeks.

Once patients agreed to participate in the study by signing the informedconsent document, a full medical and psychiatric history was taken and aphysical examination was performed by a board-certified psychiatrist.Screen rating scales were performed. Screened and eligible patients wereasked to return one week later for a baseline visit when they arerandomized to double-blind treatment with placebo or low dosenaltrexone, with the study design outlined above. The study lasted sixweeks, during which patients were assessed weekly. Subjects wereassigned randomization numbers in consecutive order. The randomizationlist was provided by a computer-generated random-number list and wasmaintained by the research pharmacist. In addition, the presence of anyside effect or adverse event was carefully documented with theSAFTEE-SI. Reasons for premature discontinuation, including change inprimary medications, were recorded.

All concomitant medications taken during the study were recorded in thecase report form, along with dosage information and start and stopdates. Medication management and clinical ratings were performed by thestudy clinicians.

At the end of the double-blind study, both responders and non-responderswho completed the double-blind phase had the option of receivingopen-label adjunctive treatment with low dose naltrexone. Subjects whoagreed to receive open-label treatment with low dose naltrexone for 3months were seen monthly by a board-certified psychiatrist until the endof the follow-up phase. Subjects who completed or refused follow-up wereoffered a referral to a psychiatrist.

The primary efficacy measurement was the change in 17-item HamiltonRating Scale for Depression (HAM-D-17) score or the 28-item HamiltonRating Scale for Depression (HAM-D-28). Secondary measures of efficacyinclude change in CGI-severity, with clinical or CGI-improvement(CGI-I). An additional measure of efficacy was the change inMontgomery-Asberg Depression Rating Scale (MADRS-10 or MADRS-15).

The following instruments were administered according to the studyschedule: a structured clinical interview for DSM-IV, an antidepressanttreatment history questionnaire, the 17-item or 28-item HamiltonDepression Scale (HAM-D-17 or HAM-D-28), Clinical GlobalImpressions—severity and improvement (CGI-S, CGI-I), 10-item or 15-itemMontgomery-Asberg Depression Rating Scale (MADRS-10 or MADRS-15), Quickinventory Depressive Symptomatology (Self Report) (QIDS-SR), a cognitiveand physical functioning questionnaire, a sexual functioningquestionnaire, the Quality of Life Satisfaction Questionnaire-short form(Q-LES-Q), and the Sheehan Disability Scale.

Low dose naltrexone showed specific efficacy for the treatment of“breakthrough depression,” an umbrella term, which encompassesdepressive relapse (a depressive episode within 6 months ofantidepressant response) and recurrence (a depressive episode after 6months of response). Patients with breakthrough depression (BTD) on anantidepressant regimen containing a pro-dopaminergic agent assigned totreatment with low dose naltrexone (1 mg bid) demonstrated higher ratesof response on all outcome measures. See figures for statisticalanalysis (e.g. FIGS. 1A, 2A, 3A, 4A, 5A, and 6A). The response to activedrug continued during the entire six week trial period (e.g. FIGS. 1B,2B, 3B, 4B, 5B, and 6B).

Additionally, patients with BTD on an antidepressant regimen containinga pro-dopaminergic agent assigned to treatment with low dose naltrexoneexperienced no significant differences in the number of adverse events,as measured by the SAFTEE-SI as well as greater improvement in Qualityof Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q) and SheehanDisability Scale (SDS) scores, compared to placebo controls.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

INCORPORATION BY REFERENCE

All patents and publications referenced herein are hereby incorporatedby reference in their entireties.

What is claimed is:
 1. A method of treating or preventing breakthroughdepression, comprising administering a therapeutically effective lowdose amount of naltrexone to a patient in need thereof.
 2. The method ofclaim 1, wherein the therapeutically effective low dose amount ofnaltrexone is administered in conjunction with a patient's pre-existentanti-depression treatment, wherein the pre-existent anti-depressiontreatment comprises one or more of a dopamine active anti-depressantagent, a dopamine active augmenting agent, a serotonin-norepinephrinereuptake inhibitor (SNRI), and a selective serotonin re-uptake inhibitor(SSRI).
 3. The method of claim 1 or 2, wherein breakthrough depressioncomprises depressive relapse and/or recurrence.
 4. The method of claims1-3, wherein the therapeutically effective low dose amount of naltrexoneis administered at doses that reverse or prevent desensitization of adopamine receptor.
 5. The method of claim 4, wherein the dopaminereceptor is one or more of the D₂ and D₃ receptors.
 6. The method ofclaims 1-5, wherein the therapeutically effective low dose amount ofnaltrexone is administered at doses that are substantially below levelsthat induce significant opioid blockade.
 7. The method of claim 4 or 6,wherein the amount of naltrexone administered is less than 10 mg.
 8. Themethod of claim 4 or 6, wherein the amount of naltrexone administered isabout 1-4 mg.
 9. The method of claim 4 or 6, wherein the amount ofnaltrexone administered is about 1 mg.
 10. The method of claims 2-9,wherein the dopamine active anti-depressant agent is one or more ofbupropion, aripiprazole, and sertraline.
 11. The method of claim 2-9,wherein the SNRI is selected from duloxetine, venlafaxine, nefazodone,and milnacipran.
 12. The method of claim 2-9, wherein the dopamineactive augmenting agent is one or more of an amphetamine salt,pramipexole, and ropinirole.
 13. The method of claim 2-9, wherein theSSRI is selected from citalopram, dapoxetine, s-citalopram, fluoxetine,fluvoxamine, indalpine, paroxetine, and zimelidine.
 14. The method ofany of the above claims, wherein the preventing or treating breakthroughdepression comprises reduction in length of a depressive episode. 15.The method of any of the above claims, wherein the preventing ortreating breakthrough depression comprises recovery of ananti-depressive effect of the patient's pre-existent anti-depressiontreatment regimen.
 16. The method of any of the above claims, whereinthe preventing or treating breakthrough depression comprises a reductionin the rate of relapse after major depressive episodes.
 17. The methodof any of the above claims, wherein the preventing or treatingbreakthrough depression comprises prevention or reversal of loss ofefficacy of the patient's pre-existent anti-depression treatment. 18.The method of any of the above claims, wherein the preventing ortreating breakthrough depression comprises reduction in an effectivedosage of the patient's pre-existent anti-depression treatment.
 19. Themethod of claim 18, wherein the reduction in an effective dosage of thepatient's pre-existent anti-depression treatment causes one or more of areduction in side effects and increase in patient adherence.
 20. Themethod of any of the above claims, wherein the therapeutically effectivelow dose amount of naltrexone is administered orally or subcutaneously.21. A method of preventing or treating treatment-refractory depression,comprising administering a therapeutically effective low dose amount ofnaltrexone to a patient in need thereof.
 22. The method of claim 21,wherein the therapeutically effective low dose amount of naltrexone isadministered in conjunction with a patient's pre-existentanti-depression treatment, wherein the pre-existent anti-depressiontreatment comprises one or more of a dopamine active anti-depressantagent, a dopamine active augmenting agent, a serotonin-norepinephrinereuptake inhibitor (SNRI), and a selective serotonin re-uptake inhibitor(SSRI).
 23. The method of claim 21 or 22, wherein treatment-refractorydepression comprises depressive relapse and/or recurrence.
 24. Themethod of claims 21-23, wherein the therapeutically effective low doseamount of naltrexone is administered at doses that reverse or preventdesensitization of a dopamine receptor.
 25. The method of claim 24,wherein the dopamine receptor is one or more of the D₂ and D₃ receptors.26. The method of claims 21-25, wherein the therapeutically effectivelow dose amount of naltrexone is administered at doses that aresubstantially below levels that induce significant opioid blockade. 27.The method of claim 24 or 26, wherein the amount of naltrexoneadministered is less than 10 mg.
 28. The method of claim 24 or 26,wherein the amount of naltrexone administered is about 1-4 mg.
 29. Themethod of claim 24 or 26, wherein the amount of naltrexone administeredis about 1 mg.
 30. The method of claim 22-29, wherein the dopamineactive anti-depressant agent is one or more of bupropion, aripiprazole,and sertraline.
 31. The method of claim 22-29, wherein the SNRI isselected from duloxetine, venlafaxine, nefazodone, and milnacipran. 32.The method of claim 22-29, wherein the dopamine active augmenting agentis one or more of an amphetamine salt, pramipexole, and ropinirole. 33.The method of claim 22-29, wherein the SSRI is selected from citalopram,dapoxetine, s-citalopram, fluoxetine, fluvoxamine, indalpine,paroxetine, and zimelidine.
 34. The method of any of the above claims,wherein the preventing or treating treatment-refractory depressioncomprises reduction in length of a depressive episode.
 35. The method ofany of the above claims, wherein the preventing or treatingtreatment-refractory depression comprises recovery of an anti-depressiveeffect of the patient's pre-existent anti-depression treatment regimen.36. The method of any of the above claims, wherein the preventing ortreating treatment-refractory depression comprises a reduction in therate of relapse after major depressive episodes.
 37. The method of anyof the above claims, wherein the preventing or treatingtreatment-refractory depression comprises prevention or reversal of lossof efficacy of the patient's pre-existent anti-depression treatment. 38.The method of any of the above claims, wherein the wherein thepreventing or treating treatment-refractory depression comprisesreduction in an effective dosage of the patient's pre-existentanti-depression treatment.
 39. The method of claim 38, wherein thereduction in an effective dosage of the patient's pre-existentanti-depression treatment causes one or more of a reduction in sideeffects and increase in patient adherence.
 40. The method of any of theabove claims, wherein the effective amount of low dose naltrexone isadministered orally or subcutaneously.
 41. A method of preventing ortreating breakthrough depression, comprising administering a combinationof a therapeutically effective low dose amount of naltrexone and atherapeutically effective amount of one or more of a dopamine activeanti-depressant agent, a dopamine active augmenting agent, aserotonin-norepinephrine reuptake inhibitor (SNRI), and a selectiveserotonin re-uptake inhibitor (SSRI) to a patient in need thereof. 42.The method of claim 41, wherein the combination is administered inconjunction with a patient's pre-existent anti-depression treatment,wherein the pre-existent anti-depression treatment comprises one or moreof a dopamine active anti-depressant agent, a dopamine active augmentingagent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and aselective serotonin re-uptake inhibitors (SSRI).
 43. The method of claim41 or 42, wherein breakthrough depression comprises depressive relapseand/or recurrence.
 44. The method of claims 41-43, wherein the low dosenaltrexone is administered at doses that reverse or preventdesensitization of a dopamine receptor.
 45. The method of claim 44,wherein the dopamine receptor is one or more of the D₂ and D₃ receptors.46. The method of claims 41-45, wherein the therapeutically effectivelow dose amount of naltrexone is administered is administered at dosesthat are substantially below levels that induce significant opioidblockade.
 47. The method of claim 44 or 46, wherein the amount ofnaltrexone administered is less than 10 mg.
 48. The method of claim 44or 46, wherein the amount of naltrexone administered is about 1-4 mg.49. The method of claim 44 or 46, wherein the amount of naltrexoneadministered is about 1 mg.
 50. The method of claims 41-49, wherein thedopamine active anti-depressant agent is one or more of bupropion,aripiprazole, and sertraline.
 51. The method of claim 41-49, wherein theSNRI is selected from duloxetine, venlafaxine, nefazodone, andmilnacipran.
 52. The method of claims 41-49, wherein the dopamine activeaugmenting agent is one or more of an amphetamine salt, pramipexole, andropinirole.
 53. The method of claims 41-49, wherein the SSRI is selectedfrom citalopram, dapoxetine, s-citalopram, fluoxetine, fluvoxamine,indalpine, paroxetine, and zimelidine.
 54. The method of claims 41-49,wherein the preventing or treating breakthrough depression comprisesreduction in length of a depressive episode.
 55. The method of claims41-49, wherein the preventing or treating breakthrough depressioncomprises recovery of the anti-depressive effect of the patient'spre-existent anti-depression treatment regimen.
 56. The method of any ofthe above claims, wherein the preventing or treating breakthroughdepression comprises a reduction in the rate of relapse after majordepressive episodes.
 57. The method of any of the above claims, whereinthe preventing or treating breakthrough depression comprises preventionor reversal of loss of efficacy of the patient's pre-existentanti-depression treatment.
 58. The method of any of the above claims,wherein the wherein the preventing or treating breakthrough depressioncomprises reduction in an effective dosage of the patient's pre-existentanti-depression treatment.
 59. The method of claim 58, wherein thereduction in an effective dosage of the patient's pre-existentanti-depression treatment causes one or more of a reduction in sideeffects and increase in patient adherence.
 60. The method of any of theabove claims wherein the effective amount of low dose naltrexone isadministered orally or subcutaneously.
 61. The method of claims 41-60,wherein the naltrexone and one or more of a dopamine activeanti-depressant agent, a dopamine active augmenting agent, aserotonin-norepinephrine reuptake inhibitor (SNRI), and a selectiveserotonin re-uptake inhibitors (SSRI) are co-formulated in a singledosage form.
 62. The method of claim 41, wherein the dosage form is anoral dosage form.
 63. The method of claim 41, wherein the dosage form isa subcutaneous dosage form.
 64. A method of preventing or treatingtreatment-refractory depression, comprising administering a combinationof a therapeutically effective low dose amount of naltrexone and atherapeutically effective amount of one or more of a dopamine activeanti-depressant agent, a dopamine active augmenting agent, aserotonin-norepinephrine reuptake inhibitor (SNRI), and a selectiveserotonin re-uptake inhibitor (SSRI) to a patient in need thereof. 65.The method of claim 64, wherein the combination is administered inconjunction with a patient's pre-existent anti-depression treatment,wherein the pre-existent anti-depression treatment comprises one or moreof a dopamine active anti-depressant agent, a dopamine active augmentingagent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and aselective serotonin re-uptake inhibitors (SSRI).
 66. The method of claim64 or 65, wherein treatment-refractory depression comprises depressiverelapse and/or recurrence.
 67. The method of claims 64-66, wherein thelow dose naltrexone is administered at doses that reverse or preventdesensitization of a dopamine receptor.
 68. The method of claim 67,wherein the dopamine receptor is one or more of the D₂ and D₃ receptors.69. The method of claims 64-68, wherein the low dose naltrexone isadministered at doses that are substantially below levels that inducesignificant opioid blockade.
 70. The method of claim 67 or 69, whereinthe amount of naltrexone administered is less than 10 mg.
 71. The methodof claim 67 or 69, wherein the amount of naltrexone administered isabout 1-4 mg.
 72. The method of claim 67 or 69, wherein the amount ofnaltrexone administered is about 1 mg.
 73. The method of claims 64-72,wherein the dopamine active anti-depressant agent is one or more ofbupropion, aripiprazole, and sertraline.
 74. The method of claim 64-73,wherein the SNRI is selected from duloxetine, venlafaxine, nefazodone,and milnacipran.
 75. The method of claims 64-73, wherein the dopamineactive augmenting agent is one or more of an amphetamine salt,pramipexole, and ropinirole.
 76. The method of claims 64-73, wherein theSSRI is selected from citalopram, dapoxetine, s-citalopram, fluoxetine,fluvoxamine, indalpine, paroxetine, and zimelidine.
 77. The method ofclaims 64-73, wherein the preventing or treating treatment-refractorydepression comprises reduction in length of a depressive episode. 78.The method of claims 64-73, wherein the preventing or treatingtreatment-refractory depression comprises recovery of theanti-depressive effect of the patient's pre-existent anti-depressiontreatment regimen.
 79. The method of claims 64-73, wherein thepreventing or treating treatment-refractory depression comprises areduction in the rate of relapse after major depressive episodes. 80.The method of claims 64-73, wherein the preventing or treatingtreatment-refractory depression comprises prevention or reversal of lossof efficacy of the patient's pre-existent anti-depression treatment. 81.The method of claims 64-73, wherein the wherein the preventing ortreating treatment-refractory depression comprises reduction in aneffective dosage of the patient's pre-existent anti-depressiontreatment.
 82. The method of claim 81, wherein the reduction in aneffective dosage of the patient's pre-existent anti-depression treatmentcauses one or more of a reduction in side effects and increase inpatient adherence.
 83. The method of claim 64 or 65, wherein theeffective amount of low dose naltrexone is administered orally.
 84. Themethod of claim 64 or 65, wherein the naltrexone and one or more of adopamine active anti-depressant agent, a dopamine active augmentingagent, a serotonin-norepinephrine reuptake inhibitor (SNRI), and aselective serotonin re-uptake inhibitors (SSRI) are co-formulated in asingle dosage form.
 85. The method of claim 64, wherein the dosage formis an oral dosage form.
 86. The method of claim 64, wherein the dosageform is a subcutaneous dosage form.
 87. The methods of claim 64 or 65,where the outcome is rapid antidepressant response compared to the usuallatency for response to traditional antidepressant pharmacotherapy. 88.The method of claim 87, wherein the rapid antidepressant response isless than about 10 days.
 89. The method of claim 87, wherein the usuallatency for response to traditional antidepressant pharmacotherapy isabout 3-6 weeks.
 90. A method of treating breakthrough depression,comprising administering a therapeutically effective low dose amount ofnaltrexone to a patient in need thereof, wherein: the patient is on anantidepressant regimen comprising a pro-dopaminergic agent and thetherapeutically effective low dose amount of naltrexone is about 1 mgbid.